The role of melatonin on radiation-induced pneumonitis and lung fibrosis: A systematic review
Graphical abstract
Introduction
Cancer or malignant tumor is characterized as the uncontrolled growth of cells and is one of the leading causes of death worldwide [[1], [2], [3]]. Moreover, a more drastic increment in its incidence and mortality has been reported worldwide [4,5]. There are several therapeutic modalities for cancer treatment which can be used as systemic, local, or targeted therapies [[6], [7], [8]].
Radiotherapy, as a local cancer treatment (for most cases), is used in 50–70% of cancer patients during their therapeutic course [[9], [10], [11]]. There are several benefits to this therapeutic modality, including non-invasiveness, organ-preservation, cost-efficiency, and spatiotemporal flexibility in tumor targeting [[12], [13], [14]]. Despite its beneficial effects for cancer control, there are some concerns related to decreasing radiotherapeutic efficiency due to induce the acute and/or late adverse effects in normal organs/tissues [15]; as some complications can affect the quality of life of irradiated patients, resulting to decrease the cost-effectiveness of radiotherapy [16,17]. Even when radiotherapy is curative, the normal tissue complications lead to suffering long-term survivors [18]. In some cases, damage to normal tissues (particularly highly radiosensitive tissues) may stop the treatment course due to acute reactions or restrict to deliver the sufficient radiation dose to the tumor [19].
The lung is considered as an organ sensitive to ionizing radiation and late responding in the body [20]. Following the exposure of this radiosensitive organ to a high radiation dose, several cytokines and chemokines are released which lead to the infiltration of inflammatory cells [21]. In addition, macrophages, neutrophils, and are able to release several cytokines which result to mediate that result in mediating the appearance of edema and pneumonitis [22]. Furthermore, chronic production of free radicals, including reactive oxygen species (ROS) and reactive nitrogen species (RNS) leads to stimulate collagen deposition in extracellular space, inducing fibrosis [23]. Both pneumonitis and lung fibrosis can lead the irradiated person to death [24]. Therefore, special attention should be considered to minimize damage to the lung tissue and effectively deliver the radiation dose to the tumor. Some studies have been performed to alleviate radiation-induced pneumonitis and fibrosis. In this regard, neutralization of free radicals, attenuation of pro-oxidant and pro-inflammatory mediators induced by ionizing radiation has been proposed for protection against pneumonitis and fibrosis [25]. Or, the use of agents such as captopril and flaxseed which are able to suppress renin-angiotensin system and oxidative stress can attenuate the signs related to pneumonitis and fibrosis [26,27].
In the past several decades, the use of radio-protector and/or radio-sensitizer agents for the alleviation of radiation-induced adverse effects has attracted much attention. Melatonin, as an indole-derived hormone, is mainly generated and secreted by the pineal gland. This hormone has various impacts on the normal tissues such as anti-oxidant, anti-inflammatory, and anti-apoptotic effects; hence, it can protect the normal tissues against oxidative and inflammatory damage [[28], [29], [30]]. Briefly, melatonin exerts an anti-oxidative action via two mechanisms of direct and indirect. In the direct pathway, this agent mostly exerts its anti-oxidant effect via radical adduct formation, single electron transfer, and hydrogen transfer [31,32]. In the indirect pathway, melatonin can stimulate anti-oxidant enzymes, protect anti-oxidant enzymes against oxidative damage, modulate genomic expressions, and so on [33,34]. Additionally, melatonin can markedly decrease pro-apoptotic factors and also increase anti-apoptotic factors [35]. The anti-inflammatory effect of melatonin is exerted by modulation of inflammatory cytokine expression levels, inflammatory mediators, infiltration of inflammatory cells, etc. [29,36].
A systematic search was performed on the potential protective role of melatonin on radiation-induced pneumonitis and lung fibrosis in the current study. Furthermore, we tried to discuss: 1) the mechanisms underlying radiation-induced pneumonitis and lung fibrosis, and 2) the mechanisms related to the radio-preventive role of melatonin.
Section snippets
Search strategy
In the present study, we performed a systematic search in accordance with the guideline of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [37]. The literature search was carried out to assessed all relevant studies on “the role of melatonin on radiation-induced pneumonitis and lung fibrosis” in both medical subject heading (MeSH) or advance on electronic databases of Web of Science (WOS), Embase, PubMed, and Scopus up to January 2021 using the keywords of
Literature search and screening
Fig. 1 is shown the process of study selection.
A systematic search found Eighty-one articles on the above-mentioned electronic databases up to January 2021. After removing the duplicated articles (n = 41), the remaining ones (n = 40) were screened in titles and abstracts, and 29 of them were omitted. Eleven articles were qualified for assessment of their full-texts. Considering the inclusion and exclusion criteria, eight articles were included in the current systematic review. Table 1
Discussion
In the present study, the potential protective effects of melatonin on radiation-induced pneumonitis and lung fibrosis were systematically reviewed. The obtained results have been represented in Table 1. Additionally, some of the important alterations following lung irradiation as well as the effects of melatonin on these changes are shown in Fig. 2.
The irradiation of the lungs (as radiosensitive organs) during radiotherapy of thorax and chest wall tumors is inevitable [46,47]. The extent of
Perspective of future research
Pneumonitis and lung fibrosis are the most common compliances of lung irradiation to high doses. These adverse effects induced by ionizing radiation can affect life quality and lead to irradiated patients' death. In this regard, researchers have suggested that the use of radio-protective agents can ameliorate radiation-induced lung injuries. The results of some in-vivo and in-vitro studies have revealed that melatonin, via anti-oxidant and anti-inflammatory actions, is able to alleviate
Conclusion
Lungs are organs sensitive to ionizing radiation and lung irradiation can induce the injuries such as pneumonitis and lung fibrosis. The pre/post-treatment with melatonin could alleviate the radiation-induced pneumonitis and lung fibrosis through its anti-oxidant and anti-inflammatory effects. Melatonin through upregulation of some enzymes such as catalase, SOD, GSH, NOX2, NOX4, DUOX1, and DUOX2 and downregulation of MDA reduced oxidative stress following lung irradiation. Moreover, melatonin
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
CRediT authorship contribution statement
S.Sh. and T.A. gave the idea and drafted some parts of the manuscript. RA-F., A.B. and M.D-G did the literature search and drafted figures. H.Z., Gh.A. and M.M. drafted some parts of the manuscript. B.F. gave the idea, edited the manuscript, and supervised the whole study. All authors read and approved the manuscript.
Declaration of competing interest
The authors declare that there are no conflicts of interest.
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